Method and therapeutic/cosmetic topical compositions for the treatment of rosacea and skin erythema using a1-adrenoceptor agonists

ABSTRACT

The present invention is directed to the treatment of skin erythema as exhibited in rosacea and other conditions characterized by increased erythema (redness) of the skin. These conditions exhibit dilation of blood vessels due to a cutaneous vascular hyper-reactivity. In particular, the present invention is directed to a novel composition and method for the treatment of skin erythema using α 1 -adrenergic receptor (α 1 -adrenoceptor) agonists incorporated into cosmetic, pharmacological or dermatological compositions for topical application to the skin.

FIELD OF THE INVENTION

The present invention is directed to the field of Rosacea andparticularly to treatments for Rosacea.

BACKGROUND OF THE INVENTION

Rosacea is a chronic inflammatory disease associated with dilation ofthe facial blood vessels in humans. Rosacea affects the skin of thecentral face, especially the nose, cheeks, chin and forehead. Thedisease may progress with age. Rosacea may begin in individuals lessthan 20 years of age but peaks between the ages of 40 and 50.

Early rosacea is characterized by recurrent episodes of flushing orblushing that often develop into persistent or permanent redness of theskin. Flushing may be triggered by numerous non-specific stimuliincluding sun exposure, heat, cold, alcoholic drinks, spicy foods,chemical irritation and strong emotions. With time, papules, pustules,blood vessel formation and hypertrophy of sebaceous glands may develop.Symptoms of facial discomfort can include tightness, itching, burning,warmth, stinging and/or tingling.

Classically, treatment includes anti-infectious agents, such as,metronidazole, clindamycin, precipitated sulfur, sodium sulfacetamide,benzoyl peroxide, azelaic acid, or tetracycline-class antibiotics. Butthese agents do not affect the vascular component of this condition orthe resulting skin redness. Other treatment strategies include avoidanceof triggering factors, irritating stimuli, and limiting sun exposure.

Lasers are now available to treat some of the telangiectasias andredness in rosacea. An excellent review of the currently availablelasers is found in the article: Getting the Red Out, presented in the6^(th) Annual Acne and Rosacea issue of Skin & Aging, August 2003, pages74-80. However, as is clearly stated in that review by Michael Krivda,“not all facial vessels respond to currently available laser therapies.”

Furthermore, although some telangiectasias are treatable with laser,treatment of these blood vessels with medications has been completelyineffective. James Q. Del Rosso, DO, clinical assistant professor.Department of Dermatology, University of Nevada School of Medicine, LasVegas, stated in: Medical Management of Rosacea with Topical Agents: Athorough appraisal of available treatment options and recent advances,Cosmetic Dermatology, August 2003: “Currently available medicaltherapies for rosacea have not been shown to reduce the number of facialtelangiectasias.”

Finally, there is currently no consistently effective treatment of anykind for the acute flushing and blushing of rosacea. John E. Wolf, Jr,MD, professor and chairman of the Department of Dermatology, BaylorCollege of Medicine, Houston, Tex., addressed this very issue in themeeting highlights for the Fall Clinical Dermatology Conference in LasVegas, N V, 2002. According to Dr. Wolf, “By far the mostdifficult-to-treat and challenging patients with rosacea are thepatients who flush and blush. Indeed, no therapy works consistently inthese patients.” Dr. Wolf further asserted, “In my opinion, lasers arethe most effective treatment for erythemato-telangiectatic rosacea, butI think they are much less effective for flushing and blushing patients.Some patients will respond but most do not.”

Similarly, no consistently effective treatment has existed for theredness that may develop in other forms of discreet skin erythemasparticularly those due to vascular cutaneous hyper-reactivity, includingthe redness associated with acute sunburn, chronic solar damage,inflammatory acne, or emotionally or physiologically induced erythema.These conditions may also be accompanied by itching, burning, or painwith resulting significant irritation for individuals sufferingtherefrom.

Thus, there exists a need for effective treatment of skin redness and ofthe state of vascular cutaneous hyper-reactivity as exhibited in rosaceaor discreet erythemas.

Although the cause of rosacea is still unknown, it is clear thatindividuals with this condition exhibit a cutaneous hyper-reactivitywith dilation of blood vessels of the skin. An acute dilation of bloodvessels leads to periodic episodes of flushing or blushing. The morechronic form, felt to be due to blood vessels dilating over decades andeventually remaining dilated permanently, manifests as permanent rednessof the skin or fine visible blood vessel formation (telangiectasias)within the skin.

A plethora of topical dermatological, cosmetic and pharmaceuticalpreparations and numerous methods and apparati exist for the treatmentof rosacea, however, none has been proven consistently effective intreating and/or preventing the vascular dilatation which characterizesthe erythema and flushing which are hallmarks of the disease.

A number of patents have been issued related to rosacea treatments. U.S.Pat. No. 4,837,378 to Borgman, describes a topical aqueous gelcontaining metronidazole and polyacrylic acid for the treatment ofrosacea. U.S. Pat. No. 6,174,534 to Richard et al. claims the use of acosmetic composition containing from 1-5% of a C.sub.12-C.sub.24 fattyacid, from 5 to 15% of an ester of C.sub.12-C.sub.24 fatty acid and of aC.sub.2-C.sub.3 polyalkylene oxide fragment containing from 2 to 100polyalkylene oxide residues, from 1 to 20% of an optionallypolyoxyalkylenated C.sub.12-C.sub.22 fatty acid glyceride containingfrom 0 to 20 ethylene oxide residues, from 1 to 20% of an ester of aC.sub.12-C.sub.24 fatty acid and of a C.sub.1-C.sub.6 alcohol, from 0.1to 10% of glycerol, from 0.1 to 3% of a C.sub.12-C.sub.24 fatty alcoholand water, where the composition is free of metronidazole, lanthanide,tin, zinc, manganese, yttrium, cobalt, barium strontium salt, andnon-photosynthetic filamentous bacteria.

U.S. Pat. No. 5,972,993 describes a method of treating rosacea with atopically applied compound comprising an antioxidant (“free-radicalscavenger”) mixed in an inert vehicle.

U.S. Pat. No. 5,569,651, to Garrison, et al discusses the use of acombination of salicylic acid and lactic acid to treat the sensitiveskin of rosacea.

U.S. Pat. No. 5,438,073, to Saurat, et al claims the use ofdermatological compositions containing retinoids for the treatment ofrosacea.

U.S. Pat. No. 6,180,699 to Tamarkin, et al claims the use ofdermatological preparations containing mono or diesters of alpha, omegadicarboxylic adds for the treatment of the hyperkeratinization andseborrheic components of rosacea.

U.S. Pat. No. 6,176,854 to Cone, claims the use of a Holmium lasersystem for the coagulation of some of the dilated blood vesselsassociated with rosacea to attempt to decrease the redness of thecondition.

U.S. Pat. No. 6,306,130 describes the use of a methods and apparati forheating and inducing necrosis and degradation of blood vessels with anexternal energy source (e.g. a laser) to permanently weld blood vesselsand treat various conditions such as varicose veins and telangiectasias.

Additionally, new insights and theories regarding the pathogenesis ofrosacea have led to the development of treatment strategies focusing onthe role of neurotransmitters and other potential mediators of vasculardilatation and hyper-reactivity.

U.S. Pat. No. 5,958,432 to Breton, et al. describes the use ofcosmetic/pharmaceutical compositions comprised of an effective SubstanceP antagonist of at least one beta-adrenergic agonist for the treatmentof a variety of mammalian disorders mediated by an increase in thesynthesis and/or release of Substance P including cutaneous disordersand sensitive skin and may generally relieve the irritation of rosacea(but has no direct vasoconstrictive properties).

U.S. Pat. No. 5,932,215 to de Lacharriere et al. is directed to thedevelopment of therapeutic/cosmetic compositions comprising CGRP(calcitonin gene related peptide) antagonists, Substance P antagonists,for treating skin redness, rosacea and discrete erythema afflicting amammalian, notably human patient. Individuals are treated byadministrating a therapeutically/cosmetically effective amount of atleast one CGRP antagonist, advantageously in combinatory mixture with atleast one antagonist of a neuropeptide other than CGRP, e.g., asubstance P antagonist, and/or at least one inflammation mediatorantagonist.

The notion of administering alpha-2 adrenoceptor agonists to alleviatethe symptoms of diseases modulated by activity of these receptors hasbeen investigated. U.S. Pat. No. 5,916,900 to Cupps, et al. relates tothe use of certain substituted 7-(2-imidazolinylamino)quinolonecompounds which have been found to be alpha-2 adrenoreceptor agonistsand are useful for the treatment of disorders modulated by alpha-2adrenoceptors. Such disorders include sinusitis, nasal congestion,numerous pulmonary and cardiovascular disorders, gastrointestinaldisorders such as diarrhea, irritable bowel syndrome and peptic ulcer,conditions associated with chronic pain, migraine, and substance-abusewithdrawal syndrome. The subject invention involved novel compounds andcompositions which have activity when administered perorally,parenterally, intranasaly and/or topically.

Finally, α₁-adrenoceptor agonists have been historically used on ocularmucosal tissue to treat the conjunctival redness associated withallergic and other conditions, and to nasal mucosa as a decongestant forthe treatment of allergic rhinitis and other conditions.

Also, U.S. Pat. No. 6,136,337 provides a composition for rectal mucosaladministration suitable for curing hemorrhoids which includes an acrylicacid polymer, a vasoconstrictor, including tetrahydrozolinehydrochloride, naphazoline hydrochloride, phenylepherine hydrochlorideor oxymetazoline hydrochloride and a rectal tissue-curing agent.

Critical to understanding the effects of catecholamines and relatedsympathomimetic agents is an understanding of the classification andproperties of the different types of adrenergic receptors(adrenoceptors) that mediate their response. Although structurallyrelated, different adrenoceptors regulate distinct physiologicalprocesses by controlling the synthesis or release of a variety of secondmessenger chemicals or compounds.

Additional general references of interest are set forth below.

-   Cross, E. Transdermal penetration of vasoconstrictors-present    understanding and assessment of the human epidermal flux and    retention of free bases and ion-pairs. Pharm Res. 2003 February;    20(2):270-4.-   Daly, C J et al. Cellular Localization and Pharmacological    Characterization of Functioning Alpha-1 Adrenoceptors by Fluorescent    Ligand Binding and Image Analysis Reveals Identical Binding    Properties of Clustered and Diffuse Populations of Receptors.    Pharmacology and Experimental Therapeutics. 1998; 286(2):984-990.-   Del Rosso, J Q. Medical Management of Rosacea With Topical Agents: A    Thorough Appraisal of Available Treatment Options and Recent    Advances. Cosmetic Dermatology. 2003; 16(8):47-55.-   Hoffman B: Catecholamines, Sympathomimetic Drugs, and Adrenergic    Receptor Antagonists, in Goodman & Gilman's The Pharmacological    Basis of Therapeutics, Tenth Edition, edited by Hardman J and    Limbird L. New York, N.Y., McGraw-Hill, 2001, pp. 215-249.-   Hoffman B and Taylor P: Neurotransmission: The Autonomic and Somatic    Motor Nervous Systems, in Goodman & Gilman's The Pharmacological    Basis of Therapeutics, Tenth Edition, edited by Hardman J and    Limbird L. New York, N.Y., McGraw-Hill, 2001, pp. 129-153.-   Hudson, A L et al. In vitro and in vivo approaches to the    characterization of the alpha2-adrenoceptor. J Auton Pharmacol. 1999    December; 19(6):11-20.-   Krivda, M. Getting the Red Out. Skin & Aging. 6^(th) Annual Acne &    Rosacea Issue. 2003; 11(8):74-80.

Odom R B et al. Andrews' Diseases of the Skin, Ninth Edition,Philadelphia, W.B. Saunders, 2000, pp 301-303.

-   Plewig, G et al: Rosacea, in Fitzpatrick's Dermatology in General    Medicine, Fifth Edition, edited by Irwin Freedberg et al. New York,    N.Y., McGraw-Hill, 1999, pp 785-794.-   Wolf J. ‘Toughest Patients’ May Be the Ones You See Each Day. in    Meeting Highlights: 21^(st) Anniversary Fall Clinical Dermatology    Conference, Las Vegas, Nev., 2002: p. 1-4.

α-Adrenoceptor Subtypes

Initially classified as either α or β subtype receptors, based onanatomical location and functional considerations, more recentpharmacological and molecular biological techniques have identified theheterogeneity of the receptors and led to the identification of numeroussubtypes of each receptor, α-adrenoceptors exist on peripheralsympathetic nerve terminals and are divided into two subtypes, α₁ andα₂. α₁ is found mostly postsynaptically, while α₂, although typicallysited presynaptically, can also occur postsynaptically. These initialsubtypes were further divided into α_(1A), α_(1B), and α_(1D) receptors(by pharmacological methods), each with distinct sequences and tissuedistributions, and α_(1a), α_(1b), and aid by molecular biological andcloning techniques (note lower case letters refer to cloned receptors).Similarly, work done to identify subtypes of the α₂ adrenoeceptor hasled to the discovery of a subclasses α_(2A), α_(2B), and α_(2C), α_(2D),and α_(2C10).

α₁-Adrenoceptor Location and Function

-   -   α₁-adrenoceptors are found both in the central and peripheral        nervous system. In the Central Nervous System they are found        mostly postsynaptically and have an excitatory function.        Peripherally, they are responsible for contraction and are        situated on vascular and non-vascular smooth muscle.        α₁-adrenoceptors on vascular smooth muscle are located        intrasynaptically and function in response to neurotransmitter        release. For non-vascular smooth muscle, they can be found on        the liver, where they cause hepatic glycogenolysis and potassium        release. On heart muscle they mediate a stimulatory (positive        inotropic) effect. In the gastrointestinal system they cause        relaxation of gastrointestinal smooth muscle and decrease        salivary secretion.

Transduction Mechanisms

All α-adrenoceptors use G-proteins as their transduction mechanism.Differences occur in the type of G-protein the receptors are coupled to.α₁-adrenoceptors are coupled through the Gp/Gq mechanism, whereasα₂-adrenoceptors are coupled through different G-proteins. Gp/Gqactivates phospholipase C that phosphorolates phosphatidyl inositol toproduce inositol triphosphate and diacylglycerol. These compounds act assecond messengers and cause release of calcium from intracellular storesin the sarcoplasmic reticulum, and activation of calcium channelsrespectively. They thus produce their effects by the release of calciumfrom intracellular stores.

Clinical Uses

The clinical uses of adrenergic compounds are vast. The treatment ofmany medical conditions can be attributed to the action of drugs actingon adrenergic receptors. For example, α-adrenoceptor ligands can be usedin the treatment of hypertension. Drugs such as prazosin, anα₁-adrenoceptor antagonist and clonidine, an α₂-adrenoceptor agonistboth have antihypertensive effects, α₁-adrenoceptor antagonists are alsoemployed in the treatment of benign prostatic hypertrophy.

Several sympathomimetic drugs are used primarily as vasoconstrictors forlocal application to nasal and ocular mucous membranes (see Table 1).α-adrenoceptor agonists are used extensively as nasal decongestants inpatients with allergic or vasomotor rhinitis and in acute rhinitis inpatients with upper respiratory infections (EMPEY and MEDDER, 1981).These drugs probably decrease the resistance to airflow by decreasingthe volume of the nasal mucosa. The receptors that mediate this effectappear to be the α₁-adrenoceptors, though α₂-adrenoceptors may beresponsible for contraction of arterioles that supply the nasal mucosa.While a major limitation of therapy with nasal decongestants is that ofa loss of efficacy with prolonged use, agonists that are selective foral receptors may be less likely to induce mucosal damage (DEBERNARDIS etal 1987). As an ocular decongestant, to decrease swelling and redness ofthe eyes, α-adrenoceptor agonists are widely used in the treatment ofallergic conjunctivitis, whether seasonal (‘hay fever’) or perennial.

The use of a topically applied α₁-adrenoceptor agonist preparation tothe skin, however, is hitherto unknown to this art and would bedesirable to provide a method of treating skin affected by rosacea orother conditions of increased cutaneous erythema.

TABLE 1 Characterisation of α-adrenoceptors: Receptor Type α₁ α₂Selective Phenylephrine Clonidine Agonist Oxymetazoline CleubuterolSelective Doxazosin Yohimbine Antagonist Prazosin Idazoxan Agonist A =NA >> ISO A = NA >> ISO Potency Order Second PLC activation dec. cAMPvia Messengers via Gp/q causes Gi/o causes dec. and Effectors inc.[Ca²⁺]₁ [Ca²⁺]₁ Physiological Smooth Inhibition of Effect muscletransmitter contraction release Hypotension, anaesthesia,Vasoconstriction Link to IUPHAR nomenclature: alpha-1 table or alpha-2table

SUMMARY OF THE INVENTION

α₁-adrenoceptor agonist have been used to constrict blood vessels orminimize redness on ocular mucosal tissue to treat conjunctival redness,to nasal mucosa, as a decongestant for the treatment of allergicrhinitis, and for rectal mucosal administration suitable for curinghemorrhoids. However, to date it was not envisaged to useα₁-adrenoceptor agonists for treating skin redness. It has now beenobserved that α₁-adrenoceptor agonists are useful for eliciting apreventive and/or therapeutic effect on decreasing skin redness whenapplied topically to the skin.

Accordingly, it is an object of the present invention to provide a novelmethod for treating rosacea and other conditions of the skincharacterized by increased erythema (redness).

Another object of the present invention to provide novel topicalcompositions for treating rosacea and other conditions of the skincharacterized by increased erythema (redness).

It is another and more specific object of the present invention toprovide such compositions that include the formulation of at least oneα₁-adrenoceptor agonist into a cosmetic, pharmaceutical ordermatological composition for decreasing and/or preventing skin rednessand irritation as exhibited in rosacea or other conditions of the skincharacterized by increased erythema and to administer said compositionsto a mammal, notably a human, in order to treat or prevent the diseasestates indicated above.

Additionally, it is an object of the present invention to provide suchcompositions that include the formulation of at least oneα₁-adrenoceptor agonist into a cosmetic, pharmaceutical ordermatological composition for decreasing and/or preventing skin rednessand irritation as exhibited in rosacea or other conditions of the skincharacterized by increased erythema in combination and admixed withother agents known to be effective in treating other manifestations ofsaid skin conditions and to administer said compositions to a mammal,notably a human, in order to treat or prevent the manifestations of thedisease states indicated above.

The present invention is achieved by the provision of methods oftreating rosacea or other conditions of the skin characterized byincreased erythema, in a patient in need of such treatment, comprisingthe topical administration of a therapeutically effective amount of acomposition comprising at least one α₁-adrenoceptor agonist.α₁-adrenoceptor agonists include, but are not limited to, oxymetazolinehydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochlorideand phenylepherine hydrochloride. Preferably, the composition comprisesat least one α₁-adrenoceptor agonist formulated in apharmaceutically/dermatologically acceptable medium, preferably a gel,cream, lotion or solution which is preferably administered by spreadingthe gel, cream, lotion or solution onto the affected area.

Preferred embodiments may also include enhancers of cutaneouspenetration or inhibitors or regulators of cutaneous penetration asrequired to increase therapeutic efficacy and/or decrease systemicabsorption and any potential undesirable systemic effects of the activeagent(s).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention is based at least in part on the clinicalobservation that the topical application of a therapeutically effectiveamount of a composition comprising at least one α₁-adrenoceptor agonistto the skin is effective in significantly reducing or preventing theredness (erythema), flushing and sensation of warmth and discomfortwhich are hallmarks of rosacea and other conditions causing discreeterythema of the skin (e.g. acne, sunburn), and thus provides bothsubjective and objective relief of signs and symptoms of theseconditions. Prototypical al-adrenoceptor agonists include phenylepherineand oxymetazoline, but other α₁-adrenoceptor agonist agents include, butare not limited to naturally occurring and synthetically derivedcompounds based on or derived from pharmacologically similarly actingchemicals, drugs or prodrugs and derivatives thereof. Examples ofpreferred compounds which are specifically contemplated asα₁-adrenoceptor agonists suitable for use in accordance with the presentinvention include, but are not limit to e.g., the α₁-adrenoceptoragonists oxymetazoline, tetrahydrozoline, nephazoline, xylometazolineand the α₁-adrenoceptor agonists discussed in chapters 6 and 10 ofGoodman and Gilman's The Pharmacological Basis of Therapeutics, TenthEdition, edited by Hardman J and Limbird L. New York, N.Y., McGraw-Hill,2001, which is hereby incorporated by reference as though set forth infull herein, and in particular phenylepherine methoxamine,mephentermine, metaraminol, desglymidodrine, and its prodrug midodrine.

As no prior consideration of the application of α₁-adrenoceptor agonistto the skin has been contemplated or reported, for any indication,little is known of the cutaneous absorption or toxicology ofoxymetazoline used in this fashion. The manufacturers report nosignificant organ damage or general toxicity in dog, cat, rabbit ormouse about dosages close to those used in man. When administered byinjection subcutaneously, in rabbits, no drug related abnormalities oreffects on the offspring were found. In a retrospective study in man, noassociation was found between the drug and congenital disorders. Nocarcinogenicity tests have been reported. But oxymetazoline has beenused intranasaly and ophthalmicaly for decades for reducing blood flowand diminishing of swelling of the mucosa and has not been reported toeffect any systemic side effects. There is no formal data on thesubject, however. The excellent safety and efficacy profile ofoxymetazoline when used intranasaly or ophthalmicaly to effect localvasoconstriction suggested its potential use as a topically appliedvasoconstrictor to the skin for the treatment of the erythema andtelangiectasias of rosacea and other erythematous conditions of the skinand has been observed clinically by one of the applicants in hisclinical practice of dermatology. The local anti-erythema effect is thusobserved when topically applying an effective amount of anal-adrenoceptor agonist, admixed with a skin-specific penetrationenhancer and a pharmacologically acceptable vehicle for topicaladministration without causing any noticeable systemic effects. Theclinical efficacy of the applied α₁-adrenoceptor agonist compound ispredicated not only upon the agent reaching the receptors, which arelocated within the skin on vascular smooth muscle, but also on thepharmacokinetics of each particular receptor agonist. Thus the choiceand concentration of the active agent, or combination of active agents,the topical delivery system and vehicle for the active agent(s) aresignificant considerations.

Specifically, prototypical α₁-adrenoceptor agonists in the presentinvention are tetrahydrozoline and oxymetazoline, and when included inthe typical embodiment as the sole active ingredient (soleα₁-adrenoceptor agonist) are preferably used in amounts of about 0.05%up to about 30%, and preferably about 0.001% up to about 3% by weightbased on the total weight of the composition. Where both, or anadditional or different α₁-adrenoceptor agonist is admixed, toweramounts of the active compound(s) might be included. Additionally, thecarrier or vehicle of the invention will have dramatic effects on theconcentrations of the active ingredients selected. The preferredembodiments employ active ingredients in amounts effective to achieveclinical efficacy without causing systemic side effects.

The compositions according to the invention may comprise allpharmaceutical forms normally utilized for the topical route ofadministration and known to practitioners of this art includingsolutions, gels, lotions creams, ointments, foams, mousses, emulsions,microemulsions, milks, serums, aerosols, sprays, dispersions,microcapsules, vesicles and microparticles thereof. The subjectcompositions may also be formulated as solid preparations constitutingsoaps or cleansing bars. These compositions are formulated according toconventional techniques.

The term “pharmacologically/dermatologically acceptable carriers”, asused herein, means that the earner is suitable for topical applicationto the keratinous tissue, has good aesthetic properties, is compatiblewith the active agents of the present invention and any othercomponents, and will not cause any untoward safety or toxicity concerns.

The carrier can be in a wide variety of forms. For example, emulsioncarriers, including, but not limited to, oil-in-water, water-in-oil,water-in-oil-in-water, and oil-in-water-in-silicon emulsions, are usefulherein. As will be understood by the skilled artisan, a given componentwill distribute primarily into either the water or oil/silicon phase,depending on the water solubility/dispersibility of the component in thecomposition. A safe and effective amount of carrier is from about 50% toabout 99.999%, more preferably from about 70% to about 99.99%.

The composition, if desired, can contain various known bases such asexcipients, binders, lubricants, and disintegrants. If desired, it canalso contain oily materials such as various fats, oils, waxes,hydrocarbons, fatty acids, higher alcohols, ester oils, metallic soaps,animal or vegetable extracts, hydrophilic or lipophilic gelling agents,hydrophilic or lipophilic active agents, pharmaceutically effectivecomponents such as vitamins, hormones, amino adds, surfactants,colorants, dyes, pigments, fragrances, odor absorbers, antiseptics,preservatives, bactericides, humectants, thickeners, solvents, fillers,antioxidants, sequestering agents, sunscreens, or any other knowncomponents and additives as long as the effects of the present inventionare not impaired.

Examples of suitable oils includes mineral oils, plant oils such aspeanut oil, sesame oil, soybean oil, safflower oil, sunflower oil,animal oils such as lanolin or perhydrosqualene, synthetic oils such aspurcellin oil, silicone oils such as cyclomethicome among others. Fattyalcohols, fatty acids such as stearic acid and waxes such as paraffinwax, carnauba wax or beeswax may also be used as fats.

The composition may also contain emulsifying agents such as glycerylstearate, solvents such as lower alcohols including ethanol,isopropanol, and propylene glycol, hydrophilic gelling agents includingcarboxyvinyl polymers or acrylic copolymers, polyacrylamides,polysaccharides, lipophilic gelling agents or fatty acid metal saltsamong others, hydrophilic acting agents such as amino acids, sugars,starch or urea, lipophilic active agents such as retinol or tocopherol.

In some embodiments, the compositions contain one or moreα₁-adrenoceptor agonists, to act specifically on the erythematouscomponent of the condition to be treated, admixed with another agentknown to be effective in treating another manifestation of the diseasestate. For example, compositions consisting of anti-rosacea agents suchas metronidazole, precipitated sulfur, sodium sulfacetamide, or azelaicacid, which are commonly used to treat the papular and pustularcomponents of rosacea are combined with adermatologically/pharmacologically acceptable form of the subjectα₁-adrenoceptor agonist to effect treatment of both the inflammatory(papular and pustular) and erythematous manifestations of the condition.There is currently no known composition available that succeeds in thisgoal.

Other embodiments combine one or more α₁-adrenoceptor agonist withactive agents destined, in particular, for preventing and/or treatingthe erythema associated with numerous other skin complaints, conditionsand afflictions. Examples of these agents include:

1. Antirosacea agents such as metronidazole, precipitated sulfur, sodiumsulfacetamide, or azelaic acid.

2. Antibacterial agents (antibiotics) such as clindamycin phosphate,erythromycin, or antibiotics from the tetracycline family.

3. Antimycobacterial agents such as dapsone.

4. Other antiacne agents such as retinoids, or benzoyl peroxide.

5. Antiparasitic agents such as metronidazole, permethrin, crotamiton orpyrethroids.

6. Antifungal agents such as compounds of the imidazole family such asmiconazole, clotrimazole, econazole, ketoconazole, or salts thereof,polyene compounds such as amphotericin B, compound of the allylaminefamily such as terbinafine.

7. Steroidal anti-inflammatory agents such as hydrocortisonetriamcinolone, fluocinonide, betamethasone valerate or clobetasolpropionate, or non-steroidal anti-inflammatory agents such as ibuprofenand salts thereof, naproxen and salts thereof, or acetaminophen.

8. Anesthetic agents such as lidocaine, prilocaine, tetracaine,Hydrochloride and derivatives thereof.

9. Antipruriginous agents such as thenaldine, trimeprazine, orpramoxine.

10. Antiviral agents such as acyclovir.

11. Keratolytic agents such as alpha- and beta-hydroxy acids such asglycolic acid or salicylic acid, or urea.

12. Anti-free radical agents (antioxidants) such as Vitamin E (alphatocopherol) and its derivatives, Vitamin C (ascorbic acid), Vitamin A(retinol) and its derivatives, and superoxide dismutases.

13. Antiseborrheic agents such as zinc pyrithione and selenium sulfide.

14. Antihistamines such as cyproheptadine or hydroxyzine.

15. Tricyclic antidepressants such as doxepin hydrochloride.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given, it being understoodthat the same are illustrative and in no ways limitative.

The administration of compositions containing one or more alpha-1adrenoreceptor agonists elicits a marked decrease or even completedisappearance of skin redness, which is manifested both in rosacea andother discreet erythemas.

Specifically, according to the present invention, at least one alpha-1adrenoreceptor agonist is formulated into a cosmetic, pharmaceutical ordermatological composition for treating skin redness of vascular origin,evident in rosacea and/or other discreet erythemas including acne andsunburn.

The compositions of the invention will be, preferably, administeredtopically. The subjective compositions for topical application comprisea cosmetically, pharmaceutically or dermatologically acceptable medium(vehicle, diluent or carrier), namely a medium which is compatible withapplication to the skin.

The present invention is directed to the use of alpha 1 and 2adrenoreceptor agonists for treat rosacea or erythema. In oneembodiment, the invention is directed to the use alpha 1 agonists suchoxymetazoline hydrochloride as a vasoconstrictor for use with or withoutan antiacne compound. Alternative alpha 1 agonists includingPhenylephrine are applicable to the teachings of the present invention.The principles of the present invention are also deemed to be applicableto alpha 2 adrenoreceptor agonists such as Clonidine and Clenbuterol.

For the purposes of this disclosure, rosacea is characterized byerythema of the face, predominantly on the cheeks, the forehead and thenose, hyperseborrhoea of the face on the forehead, the nose and thecheeks, and an infectious component manifesting acne form pustules.Moreover, these indications are associated with a neurogenic component,namely, a cutaneous hyperreactivity of the skin of the face and of theneck, characterized by the appearance of redness and subjectivesensations of the itching or pruritus type, sensations of burning or ofheating, sensations of stinging, tingling, discomfort, tightness, etc.

The preferred alpha 1 or 2 agonist used as a vasoconstrictor in thepresent invention is preferably used in an amount of about 0.01% up toabout 20%, and preferably about 0.1% to about 10%, by weight based onthe total weight of the composition. In the most preferred embodiment,the vasoconstrictor comprises an alpha 1 or alpha 2 adrenoreceptoragonist. The vasoconstrictor used in the present invention may functionto remove the redness from acne areas of the skin, includingoxymetazoline hydrochloride, the preferred agonist in the presentinvention oxymetazoline hydrochloride: The chemical formula foroxymetazoline hydrochloride is as follows:

2-(3-Hydroxy-2,6-dimethyl-4-t-butylbenzyl)-2-imidazoline hydrochloride

Oxymetazoline Hydrochloride: Structural Formula:

The following table sets forth the characteristics of alpha 1 and alpha2 adrenoreceptors as used in the present invention.

Receptor Type α₁ α₂ Selective Phenylephrine Clonidine AgonistOxymetazoline Clenbuterol Selective Doxazosin Yohimbine AntagonistPrazosin Idazoxan Agonist A = NA >> ISO A = NA >> ISO Potency OrderSecond PLC activation dec. cAMP via Messengers via Gp/q Gl/o causes dec.and Effectors causes inc. [Ca²⁺]₁ [Ca²⁺]₁ Physiological SmoothInhibition of Effect muscle transmitter contraction release Hypotension,anaesthesia, Vasoconstriction

The present invention has been described with reference to the enclosedpreferred embodiment. The true nature and scope of the present inventionis to be determined with reference to the claims appended hereto.

1. A method of treating facial erythema associated with rosacea in ahuman subject in need of such treatment, said method comprising:administering topically to the face of the human subject, apharmaceutical composition comprising 0.001% w/w to 3% w/w ofoxymetazoline hydrochloride as the sole active ingredient and apharmaceutically acceptable carrier, wherein said pharmaceuticalcomposition is a cream.
 2. The method of claim 1, wherein saidadministering involves spreading the pharmaceutical composition over oneor more affected areas of the face.
 3. The method of claim 1, whereinsaid pharmaceutically acceptable carrier comprises about 50% to about99.999% of the composition.
 4. The method of claim 1, wherein thepharmaceutically acceptable carrier comprises one or more emulsifyingagents.
 5. The method of claim 1, wherein the pharmaceuticallyacceptable carrier comprises one or more oils.
 6. The method of claim 5,wherein the one or more oils comprise lanolin and fatty alcohols.
 7. Themethod of claim 1, wherein the pharmaceutically acceptable carriercomprises one or more preservatives, solvents, antioxidants, emulsifyingagents, oils, or combinations thereof.
 8. A method of treating erythemaassociated with rosacea in a human subject, the method comprising:administering topically to an area of skin of the human subject, apharmaceutical cream comprising 0.001% w/w to 3% w/w of oxymetazolinehydrochloride as the sole active ingredient and a pharmaceuticallyacceptable carrier, wherein the area of skin is affected by, or is proneto be affected by, persistent erythema associated with rosacea.
 9. Themethod of claim 8, wherein the area of skin affected by, or prone to beaffected by, persistent erythema associated with rosacea includescheeks, forehead, and nose of the human subject.
 10. The method of claim8, wherein said administering involves spreading the pharmaceuticalcream over the one or more areas of skin on the human subject affectedby, or prone to be affected by, persistent erythema associated withrosacea.
 11. The method of claim 8, wherein said pharmaceuticallyacceptable carrier comprises about 50% to about 99.999% of thecomposition.
 12. The method of claim 8, wherein the pharmaceuticallyacceptable carrier comprises one or more emulsifying agents.
 13. Themethod of claim 8, wherein the pharmaceutically acceptable carriercomprises one or more oils.
 14. The method of claim 13, wherein the oneor more oils comprise lanolin and fatty alcohols.
 15. The method ofclaim 8, wherein the pharmaceutically acceptable carrier comprises oneor more preservatives, solvents, antioxidants, emulsifying agents, oils,or combinations thereof.